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C-reactive Protein (CRP) and Peripheral Vein Graft Disease: Evidence for a Direct Effect on Smooth Muscle Cell (SMC) Phenotype

Karen J. Ho, Christopher D. Owens, Thomas Longo, Xin X. Sui, Cristos Ifantides, Michael S. Conte ∙ Brigham & Women's Hospital, Boston, MA

Objective: CRP is an important biomarker for atherosclerosis risk, and recent work suggests that it may correlate with vein graft failure. The role of CRP as a direct modulator of cellular function in the vessel wall remains controversial. We hypothesize that high levels of CRP within the vein may have a direct influence on SMC phenotype.

Methods: Tissue distribution of CRP in formalin-fixed, paraffin-embedded pre-bypass human saphenous veins (n=8) and failing vein grafts (n=13, 25-4400 days postop) was examined by immunohistochemistry. Neointimal, medial and wall thickness of vein grafts were quantitated on elastin-stained sections. Primary cultures of quiescent human saphenous vein SMCs were stimulated with dialyzed human CRP (5-50mg/L). Cell proliferation over 7 days was assayed using a metabolic activity assay (Alamar Blue). SMC migration was measured using a modified Boyden chamber assay with PDGF-BB (5-10 ng/mL) as the chemoattractant. SMC expression of the PDGF receptor (PDGFR) genes was examined at RNA (RT-PCR) and protein (Western blotting) levels after 24-72h of CRP exposure.

Results: CRP was minimally detectable in pre-bypass vein sections but positive staining was observed in 8/13 diseased vein grafts where it localized to the deep media and adventitial layers. Intensity of CRP staining did not correlate with graft age, neointimal or wall thickness. SMCs pre-treated with CRP demonstrated significantly increased migration to PDGF-BB (p=.02), which was inhibited by a PDGF neutralizing antibody (Figure 1). CRP did not stimulate SMC proliferation over the dose range tested. SMCs treated with CRP showed a dose-dependent increase in PDGFRβ RNA and protein expression after 24 and 48h, respectively (Figure 2), without a change in PDGF ligand expression.

Conclusions: CRP is detectable within the wall of most diseased vein grafts, where it may potentially exert local effects. Our data suggest that clinically-relevant levels of CRP can stimulate SMC migration by a mechanism that may involve upregulation of PDGFRβ expression.